The efficient, selective synthesis of reaction products wherein only one of multiple functional groups in a starting material is reacted remains a continuing challenge in organic chemistry. One such example is the selective acylation of the amino group of amino alcohols.
N-acylated amino alcohols are especially important since among these compounds sphingolipids, particularly ceramides and derivatives thereof such as cerebrosides, gangliosides and sphingomyelins are of commercial and therapeutic importance. Ceramides, for example, are of great commercial potential in cosmetics and pharmaceuticals such as hair and skin care products (Zysman, A. et al. (1991) European Patent Application Publication No. 0 420 722 A2).
Ceramides are a class of polar lipids endogenous to the epidermis. Ceramides play a major role in the water-retaining properties of the epidermis. It has been found that topical applications of ceramide- and pseudoceramide- containing compositions are effective in restoring the water content or dry skin and may be effective in relieving atopic eczema (Kerscher, M. et al. (1991) Eur. J. Dermatol., 1, 39-43; Imokawa, G. et al. (1989) J. Soc. Cosmet. Chem., 40, 273-285).
Sphingolipids have been found to exhibit therapeutic properties such as wound and ulcer healing through the promotion of cell restoration and growth (Tschannen, R. et al. (1985) European Patent Application Publication No. 0 146 810 A2).
In current practice, sphingolipids, especially ceramides, are primarily obtained via extraction and isolation from animal tissues, usually from bovine brain or porcine epidermal tissue. These extracts are primarily comprised of glycoceramides and generally contain only a few percent ceramides. Obviously, using this method, the production of ceramides is rather costly on an industrial scale. It would thus be desirable to find an alternative cost-efficient, high yield method for obtaining these valuable products.
Chemical synthesis methods may provide a suitable alternative. Sphingolipids, as mentioned above, are characterized by a fatty N-acyl moiety. The acylation of amines may be achieved via a number of methods known in the art. Among these methods, Heymes, R. et al. ((1983) European Patent No. 0 023 453 B1) described a method for the acylation of the 7-amino group of cephalosporins via the formation of a mixed anhydride by reacting the acid moiety to be coupled to the amino group with a sulfonyl halide, followed by reacting the mixed anhydride with the amino group.
EP-A-0,187,702 discloses the preparation of N-(omega, omega-1-dialkoxy)- and N-(omega, omega-1-dialkenloxy)-alk-1-yl-N,N,N-trisubstituted ammonium surfactants. In this preparation the tosylate of oleic acid can be used. Other mixed anhydrides are known from J. Org. Chem. 56 5132-8 (1991) which describes the mesityl sulfonate of 10-undecenoic acid, and from Chemical Abstracts 86 No. 89125r (1977) which discloses the tosylate of stearic acid.
EP-A-0,398,340 describes the N-acylation of 2-amino-4-octen-1,3-diol with octanoyl chloride in a two phase system.
However, sphingosine and derivatives thereof are polyfunctional compounds containing multiple free hydroxyl moieties as well as a free amino group. As mentioned above, the selective synthesis of monosubstituted compounds from starting materials having multiple functional groups present special complications not encountered in the reaction of starting materials having a single functional group. Indeed Ong, D. and Brody, R. ((1972) J. Lipid Res., 13, 819-822) teach that the acylation of compounds such as sphingenine (sphingosine) and sphinganine (dihydrosphingosine) which have more than one free hydroxyl group as well as a free amino group with fatty acid chlorides suffer from lack of selectivity and can lead to the formation of di-O-acyl-N-acyl compounds, even as compared to compounds having a free amino group and a single free hydroxyl moiety. The formation of O-acylated analogs necessitates an extra step to cleave the O-acyl linkages in order to obtain the desired monosubstituted N-acyl amino alcohol. Other attempts to refine this latter method to favor the formation of the desired N-acylated products (without concomitant formation of di-O-acyl-N-acyl compounds) provided only low yields (Weiss, B. and Raizman, P. (1958) J. Amer. Chem. Soc., 80, 4657-4658).
Thus, it can not be predicted whether the method described by Heymes et al. (supra) will lead to the selective acylation of the amino group of amino alcohols having more than one free hydroxyl moiety with good yield of the desired N-acylated product.